This is a proposal to study natural suppressor (NS) cell activity in mice. NS cells are potent inhibitors of immune responses. NS cell activity is not specific and is not MHC restricted. NS cell activity is found in several normal locations such as bone marrow and newborn spleen. It is induced and found in large quantities after cytoreductive/immunosuppressive treatments such as total lymphoid irradiation and cyclophosphamide (CY). The aim of this proposal is to study the role of natural suppressor (NC) cells in cancer therapy and in tolerance induction. The hypothesis is that NS cells are natural immunoregulators which are important to the outcome of cytoreductive therapies commonly used in cancer therapy, and as immunosuppressive treatments in transplantation. Therefore, both the CY-induced and newborn NS cell murine systems will be used--the CY system as a model of cytoreductive/immunosuppressive treatments, and the newborn system as a "normal" location of NS cells and tolerance induction. This proposal is to: 1) Investigate whether NS cells inhibit NK and LAK development and activity. 2) Develop an in vitro assay for NS cell potential which could be used to point out genetic differences in NS cell activity. 3) Study whether genetic differences in NS cell potential are linked to success or failure of cytoreductive/immunosuppressive treatments. 4) See if there are differences between high and low NS strains of mice in the success of cytoreductive treatments for cancer. 5) Investigate whether high and low NS strains of mice have differences in the success of LAK generation and therapy. 6) Study whether high NS strains of mice are more easily tolerized than low NS strains. 7) Develop NS cell clones and antibodies to them. 8) Study the mechanism of NS cell suppression.